Precise measurements of Raman spectra are necessary to help obtain accurate, corrected, reliable data on the relative intensity of these spectra, obtained by instruments that employ light of a set wavelength. Assuring accuracy in measurements is essential to research in many branches of optical physics, analytical chemistry, and allied fields; and particularly in the pharmaceutical industry and the forensics community for validation of the performance of their instruments.
NIST announces reference values for correcting the relative intensity of Raman spectra obtained with instruments that use 785-nm laser excitation in its SRM 2241 Relative Intensity Correction Standard for Raman Spectroscopy. SRM 2241 consists of an optical glass that emits a broadband luminescence spectrum when it is excited with 785-nm laser radiation. The shape of the luminescence of this glass is described by a polynomial expression that relates the relative spectral intensity to the wave number (cm−1), expressed as the Raman shift from the excitation wavelength of 785-nm. Together with a measurement of the luminescence spectrum of the standard, this polynomial can be used to determine the spectral intensity response correction that is unique to each Raman system.
The relative spectral intensity of the glass luminescence was determined through the use of a white-light, uniform-source, integrating sphere that has been calibrated for its irradiance at NIST. The instrument-intensity response correction obtained with this standard may be used to obtain Raman spectra that are instrument-independent.
SRM 2241 is intended for use in measurements over the range of 20° C.-25° C. and with Raman systems that use laser excitation at 785-nm. It also may be used for Raman excitation with lasers that range from 784-nm to 786-nm in excitation wavelength. SRM 2241 can be purchased from National Institute of Standards and Technology, Standard Reference Materials Group, 100 Bureau Drive, Stop 2322, Gaithersburg, Md. 20899-2322.
In fact, there are about as many different kinds of standards for analytical instruments as there are different kinds of instruments. SRM2241 is a material that was designed to allow standardization of Raman spectra obtained on different machines so that published spectra from different machines can be directly compared with each other. This material can be fabricated into many shapes and sizes so that it is compatible with use in various machines ranging from commercial Raman spectrometers that use cuvettes as sample holders to Raman microscopes that use microscope slides as sample holders.
Calibration standards are included with commercial finger stick based glucometers (FSGs) that permit verification of glucometer operation. Such FSG standards take the form of solutions that can be introduced into the same cuvettes that normally hold sample, i.e. capillary blood obtained via fingerstick. This approach succeeds for many analytical devices when the sample preparation and the physical form of the calibrator material can be made sufficiently similar to the intended unknown samples that virtually all the sources for error and or imprecision are checked by use of the calibrator.
SRM2241 and similar or derived materials and devices allow the user to test and calibrate the wavenumber and detection sensitivity of generic Raman instruments. However, a preferred system for noninvasive glucose monitoring, the LighTouch™ glucometer, relies on the operation of a Raman spectrometer system and also on a tissue modulation system. A LighTouch™ calibrator intended for use by lay people involved in self-monitoring of blood glucose must allow easy and safe testing of both subsystems.
The invention disclosed herein relates to novel ways to incorporate SRM2241 and similar materials into a calibrator appropriate to a user-friendly, noninvasive monitoring system, such as the LighTouch™ measurement paradigm. Also disclosed are novel calibrators unrelated to the material SRM 2241, but each having its own specific characteristic advantages for certain types of commercial systems. Multiple approaches to calibrator design are advantageous in anticipation of the continued evolution of noninvasive in vivo monitoring devices.
Noninvasive in vivo glucometers present a unique concern in that the sample holder must interface between a sensitive spectrometer and some portion of a human body. Few objects are as variable in shape and texture as the fully differentiated and integrated tissue and organ systems present in virtually any portion of the human body. The relevant portion of the human body can be regarded as a highly spatially and temporally variable optical medium. The calibrator/sample must produce a spectroscopic response that, when subjected to the same signal processing and data extraction algorithm(s) employed for handling in vivo tissue, produces a correct result. The calibrator must interact with the tissue modulation system in a manner that causes the LighTouch™ device to initiate and perform a measurement cycle.
In one embodiment of the LighTouch™ device, a measurement cycle is initiated in response to placing a particular volar side fingertip capillary bed in juxtaposition with an orifice. The proper positioning of the fingertip causes the switching of an aperture, un-shuttering the laser and providing a required eye safety function. Proper positioning is sensed by the LighTouch™ device using various measurements including, but not limited to, the average and temporal pressure/force variation on the orifice. The software and hardware of the system that interface to the sample must also function properly with either the calibrator or the in vivo sample to produce the correct answer. As disclosed herein, it is possible, using these two observables, to automatically discern between a calibration measurement cycle and a real in vivo measurement cycle.
Some noninvasive spectroscopic blood analysis strategies involve comparing a measurement of a specific person's spectroscopic response to some function of their own earlier measurements. In this way, that device is considered calibrated to that individual. One could certainly design an embodiment of some material which could be used to test the operation of the spectroscopic system of such non-tissue modulated, noninvasive glucometers. Given an appropriate material to serve as sample, the algorithm itself suggests tests that would probe the operation of the internal calibration system. There might be some induction period needed to provide some prior data for internal comparison, but other approaches might be adequate as well. Diffuse reflectance and absorption type near infrared systems probe a different part of the spectral response of the calibrator than does Raman scattering, but the calibrator of the invention could be suitable for both types of devices.
Tissue modulation in concert with difference spectroscopy and potentially other measurements isolates the spectroscopic signal from a particular component of the in vivo tissue. In this case, the sample, e.g. the capillary bed in a human fingertip or some other human tissue, is subjected to mechanical, thermal, and/or chemical stimuli chosen to induce specific spatio-temporal variations in tissue composition. For example, the mechanical response of mobile tissues such as blood and lymph to pressure far exceeds that of static structural tissues, and other bulk properties. Tissue modulation implies that the sample will be compared to itself as a part of the analog measurement process before, during, and after the stimulation. It is desirable for the calibrator to be compatible with the process and sample holder characteristics that are best suited to modulate the in vivo tissue.
Besides the specific requirements of device operation relating to laser operation and eye safety, there are other important requirements. Portable devices demand that we endeavor to keep the mechanics of initiating a calibration cycle instead of an in vivo measurement cycle transparent to the user. Lay people as well as the technically proficient should be able to use this process and device to facilitate confidence in the monitoring device. Moreover, system overhead can be reduced by avoiding front panel buttons and other higher-level input-output accessories. It is preferably easy and inexpensive to produce and dispose of many calibrators, as many may be needed.
The NIST Raman standard is designed for use by a technical professional, who would care for a primary standard calibrator more attentively than members of the general public using an at-home device for personal glucose monitoring.